Germline stem cells

Abstract

Sperm and egg production requires a robust stem cell system that balances self-renewal with differentiation. Self-renewal at the expense of differentiation can cause tumorigenesis, whereas differentiation at the expense of self-renewal can cause germ cell depletion and infertility. In most organisms, and sometimes in both sexes, germline stem cells (GSCs) often reside in a defined anatomical niche. Factors within the niche regulate a balance between GSC self-renewal and differentiation. Asymmetric division of the germline stem cell to form daughter cells with alternative fates is common. The exception to both these tendencies is the mammalian testis where there does not appear to be an obvious anatomical niche and where GSC homeostasis is likely accomplished by a stochastic balance of self-renewal and differentiation and not by regulated asymmetric cell division. Despite these apparent differences, GSCs in all organisms share many common mechanisms, although not necessarily molecules, to guarantee survival of the germline.

Figure 1.

Germline stem cell lineages: stem cell self-renewal, transit-amplifying (TA) mitotic divisions, and the switch to meiosis and gamete differentiation. (A) Germline stem cell lineage in a C. elegans hermaphrodite undergoing oogenesis. The somatic distal tip cell (DTC, red) maintains a population of germ cell nuclei in a stem cell state. As germ cell nuclei move away from the DTC they enter a mitotic TA state during which they gradually differentiate, finally switching to the meiotic program (green). (Panel adapted from Cinquin et al. [2010]; reprinted, with permission, from the National Academy of Sciences © 2010.) (B) Male germline stem cell lineage in Drosophila. A stem cell (red) at the tip of the testis divides asymmetrically, producing a new stem cell and a gonialblast, which initiates four rounds of synchronous spermatogonial mitotic TA divisions with incomplete cytokinesis. The resulting 16 interconnected germ cells undergo premeiotic DNA replication in synchrony and switch to the spermatocyte program of cell growth, meiotic prophase, and transcription of terminal differentiation genes. (All 16 cells become spermatocytes, but only one is shown for simplicity.) (C) Male germline stem cell lineage in mouse. In mice, the prevailing model (shown by black arrows) assumes that the singly isolated spermatogonia (A_s) is the predominant stem cell during steady-state spermatogenesis. However, all of the cells shown in the box, the A_s, A_pr, and A_al spermatogonia have stem cell potential. At the 16 cell-cyst stage, the A_al-16 transform without cell division into differentiating spermatogonia, which subsequently undergo six rounds of mitosis before entering meiosis. The blue arrows indicate the ability of cells to detach from cysts and revert to the A_s state. Reversion occurs frequently during regeneration following insult and following germ cell transplantation, however, it has also been observed during steady-state spermatogenesis. (Panel B is adapted from Davies and Fuller [2008]; reprinted, with permission, from Cold Spring Harbor Press © 2008.)

Figure 2.

Germline stem cell microenvironments in Drosophila ovary and Drosophila and mouse testes. (A) The Drosophila ovarian stem cell niche controls cystoblast formation. Upd secreted by terminal filament cells (light blue) activates JAK-STAT signal transduction within cap cells (dark blue) and probably in escort cells (tan), which in response produce the BMP ligands DPP and GBB (“BMP”). Receipt of these signals in germline stem cells (GSC) activates BMP signal transduction (lightning blots), which represses bam transcription. Consequently, the NANOS translational repressor remains high. (Right) A GSC daughter has differentiated into a cystoblast (CB, light green) and is surrounded by escort cells. High levels of BAM present due to derepression have translationally downregulated NANOS. Signals from the CB via the ligand Spitz (red arrow) activate EGFR signaling in escort cells, which modulate the extracellular matrix (red lines) to block residual BMP reception. (B) The apical hub and flanking somatic cyst stem cells (CySCs) contribute to the germline stem cell (GSC) niche in Drosophila testes. (Left) Unpaired (Upd) secreted by hub cells (blue) activates the Janus kinase-signal transducer and activator transcription (JAK-STAT) pathway, which requires the cell to autonomously maintain the attachment of GSCs to the hub and for self-renewal of cyst stem cells (CySC). GSC self-renewal also requires as-yet-unknown signal(s) (lightning bolt) from the CySCs. (Right) Interactions between the progeny of somatic and germline stem cells set up the functional unit of differentiation, the cyst. A gonialblast (light green), produced by asymmetric division of a GSC, signals via the epidermal growth factor receptor (EGFR) ligand Spitz, to cyst cells (light pink) produced by asymmetric division of CySCs. Activation of EGFR triggers the somatic cyst cells to envelop the gonialblast and may also induce changes in gene expression in the cyst cells required for the germ cells to execute the TA division program. (C) The microenvironment of germline stem cells in mouse testes. All spermatogonia, including the GSCs, occupy the basal compartment of the seminiferous tubules between Sertoli cell tight junctions and the basement membrane. The GSCs are biased to the area adjacent to the blood vessels and interstitial cells running between the tubules. (Panel C is adapted from Davies and Fuller [2008]; reprinted, with permission, from Cold Spring Harbor Press © 2008.)